ABSTRACT Spontaneous preterm birth (SPTB) is a major public health problem world-wide, accounting in the United States for about 10% of all live births (380,000 cases per year) with an estimated cost of nearly $30 billion per year. This proposal is focused on HLA-C, the only highly polymorphic alloantigen expressed by invading extravillous trophoblasts (EVT) at the maternal-fetal interface. HLA-C expression on EVT has a dual role as the major molecule to which maternal-fetal tolerance must be generated but also as the principal molecule involved in immune defense against viruses and bacteria in the placenta. EVT that form the fetal side of the maternal-fetal interface express a triad of HLA molecules, HLA-C, HLA-G, and HLA-E that play critical roles in maternal-fetal tolerance (but do not express the classical polymorphic HLA-A and HLA-B proteins). HLA-E that is expressed at a low level functions as an inhibitor of NK cells that express its ligand CD94/NKG2A. HLA-G is directly involved in the generation of tolerance to the killer cells (NK cells and CD8+ T cells) in the maternal decidua. HLA-E and HLA-G exhibit only minimal polymorphism, whereas HLA-C is highly polymorphic with over 3500 alleles thus far identified. HLA-C is therefore the principal molecule to which immune tolerance must be generated to prevent allogeneic rejection of the fetus. As the only polymorphic HLA molecule present at this site, it is also the main molecule able to presents peptides from pathogens to T cells. Thus HLA-C is essential for clearance of placental infections as well as in preventing pathogens from crossing the maternal-fetal interface and infecting the fetus. High HLA-C cell surface expression levels were shown to be important in the control of peripheral infections as well as development of inflammatory disease. For example, high cell surface levels of HLA-C are i) found on peripheral lymphocytes in HIV non-progressors, HIV-positive individuals who do not progress to AIDS, ii) associated with increased inflammatory responses in Crohn's disease and iii) increased the generation of cytotoxic T lymphocytes to HLA-C mismatches in hematopoietic transplant patients. These data suggest a broad influence of HLA-C expression levels in inflammation and human disease that has thus far not been investigated in the development of severe pregnancy complications. Generating high levels of HLA-C at the maternal-fetal interface may be a route to control of viruses such as human cytomegalovirus (HCMV), and diminish congenital defects associated with HCMV infection. On the other hand high HLA-C levels may increase immune recognition and generation of detrimental T cell responses that contribute to sterile inflammatory responses in the placenta and fetal membranes. Two-thirds of SPTB are associated with infection, while the other third is related to sterile inflammation. Understanding the generation and the role of HLA-C expression on EVT will therefore contribute to our understanding and possible management of pregnancy complications such as SPTB. The specific aims of this research are to investigate the unique molecular mechanism of transcriptional and posttranscriptional regulation of HLA-C expression levels on EVT and to ask whether SPTB is related to its level of expression.